5G-PEARL: Paxalisib in Malignant Brain Tumours

Inclusion Criteria: Phase 1b front line mrd cohort: 1. Patients with histologically confirmed advanced WHO Stage IV glioblastoma (per fourth edition 2016). Per the new 2021 fifth edition of WHO Classification of Tumours of the Central Nervous System, this will include: • Glioblastoma, IDH-wildtype Grade 4 2. Patients for Phase 1b will need to have consented to the Minderoo Precision Brain Tumour Programme and have whole genome, and transcriptome data available. Patients who have had NHS funded whole genome sequencing and have available frozen tissue stored can be recruited to the study in parallel to consenting to the Minderoo Precision Brain Tumour Programme to have transcriptome analysis done. 3. Patients for the minimal residual disease (mrd) cohort will be eligible following completion of optimal surgery and Stupp based adjuvant chemoradiotherapy as long as they meet all other inclusion/exclusion criteria. Patients will need to commence Cycle 1 Day 1 of the study no later than 6 weeks from the completion of chemoradiotherapy. Patients who are radiologically progressing following chemo-radiotherapy will not be eligible. 4. 16 years or over. 5. Life expectancy of at least 12 weeks. 6. World Health Organisation (WHO) performance status of 0-1. 7. Neurologically stable (eg without a progression of neurological symptoms or requiring escalating doses of systemic steroid therapy within one week prior to cycle 1, day 1. 8. Written (signed or dated) informed consent and be capable of co-operating with treatment and follow up. 9. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to the first dose of either IMP. Haemoglobin (Hb): ≥ 9.0 g/dL Absolute neutrophil count: ≥1.5 x 10\^9/L Platelet count: ≥100 x 10\^9/L Coagulation: INR \< 1.5 and APTT \<1.5x if not anticoagulated INR stable \> 7 days within intended therapeutic range if anticoagulated Bilirubin: ≤1.5 x ULN; participants with Gilbert's syndrome can enrol if conjugated bilirubin is within normal ranges. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): \<3 x ULN Albumin: ≥ 28 g/L Creatinine: \<1.5 x ULN Sodium: ≥130 mmol/L Potassium, Calcium, Magnesium, phosphate: Within institution normal ranges (replacement is permitted) HbA1C (%): \<8.0 Urinary protein: \< 1+ on dipstick 10. Female patients with reproductive potential must have a negative serum pregnancy test within 14 days prior to start of trial. 11. Men and women of childbearing potential must agree to comply with the use of a highly effective method of contraception so as to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 180 days after the last dose of either investigational drug. Please, refer to section 4.1 of the Clinical Trials Facilitation and Coordination Group (CTCG) guidance for further details. Exclusion Criteria: Phase 1b frontline mrd cohort: 1. Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable: * Bevacizumab during the prior 6 weeks * Any investigational medicinal product since diagnosis. * Tumour treating fields during the prior 6 weeks 2. Prior immune checkpoint inhibitor therapy or vaccine therapy is not permitted. Prior use of any other immune-modulatory investigational agent must be discussed with sponsor team and CI. 3. Ongoing Grade 2 or greater toxicities from pre-existing conditions or from previous treatments. 4. Patients with carcinomatous meningitis, leptomeningeal spread of tumour, spread of tumour to the brain stem or spinal cord. 5. Has evidence of recent intratumoural or peritumoural haemorrhage on baseline MRI. Patients with radiological findings that are stable on at least 2 consecutive MRI scans at least 3 weeks apart will be eligible. 6. History of clinical relevant bleeding disorders, including significant GI bleeding within last 6 months. 7. History of arterial thromboembolism. 8. Recent (within 3 months) deep vein thrombosis or pulmonary embolism or other significant thromboembolism. Venous port of catheter thrombosis or superficial thrombosis are not considered significant. Patients with prior thrombosis (\> 3 months ago) on stable anticoagulation are permitted to be enrolled. 9. History of clinically significant cardiac disorders: * Myocardial infarction, or New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug. * Concurrent and clinically significant abnormalities on electrocardiogram (ECG) at Screening, including a corrected QT interval (QTcF \>480ms). 10. History of malabsorption syndrome or other conditions that may interfere with enteral absorption. Patients with a history of or active inflammatory bowel disease (eg Crohn's disease or ulcerative colitis). History of gastrointestinal perforation or fistulae. 11. History of uncontrolled diabetes. Patients with controlled diabetes on therapy with HbA1C \<8% will be eligible. 12. Has urine protein \> 1g/24 hours. Participants with \>1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. 13. Has significant lung disease including pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, active tuberculosis, or history of opportunistic infections (including PCP or CMV pneumonia). 14. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 15. Steroid requirement for neurological symptom control of \>3mg Dexamethasone per day (patients will allowed to enrol if they have been on a stable dose of steroids of equivalent or less than 3mg Dexamethasone for at least 5 days prior to Day 1 of Cycle 1). 16. Has received a live vaccine within 30 days of planned start of study therapy. Note: inactive vaccines including COVID vaccines are allowed prior